Project Summary Calcific aortic valve stenosis (CAVS) can be viewed as the end-stage of prolonged persistent injury in valve tissue. Isolated valve interstitial cells (VICs), CAVS-prone mice, and humans with subclinical aortic valve disease all demonstrate a propensity for propagation of injury in valve tissue, even after the initiating cause is rectified. The goals of this proposal are understand mechanisms, and to identify therapeutic strategies with the potential to inhibit or reverse propagation of injury in valve tissue. Early aortic valve disease entails thickening and stiffening of valve cusps, and disruption of laminar shear at the blood-valve interface. The proposal will address the hypothesis that tissue responses to altered mechanical forces may propagate a pattern of injury in the aortic valve. Therefore, experiments proposed for Aim 1 will study modulation of signaling by the mechano-responsive calcium channel, TRPV4, as a means to inhibit propagation of injury. In other disease states, persistent tissue injury is characterized by sustained actions of mediators of inflammation, which may be amenable to inhibition by specialized pro-resolving mediators (SPMs). New preliminary data indicate that two SPMs are expressed in aortic valve cells, and that their expression is altered by CAVS-relevant conditions. Experiments proposed for Aim 2 will study the impact of modulation of those two SPMs, annexin A1 and chemokine-like receptor-1, upon propagation of injury in aortic valve cells. Both Aims will be pursued using VICs grown on matrix with mechanical properties that can be manipulated to resemble properties of aortic valves. Both Aims will be pursued using a mouse model that consistently develops CAVS, and which reaches a state where amelioration of the initiating cause of CAVS no longer inhibits disease progression. These new areas of research in aortic valve disease hold promise for translation to effective therapies for CAVS.